1. Field of the Invention
The present invention relates generally to the field of cancer prevention. In particular, the invention relates to a method of preventing colon cancer by vitamin D.sub.3 analogues. In one example, administration of 1.alpha., 25-Dihydroxy-16-ene-23-yne-26, 27-hexafluorocholecalciferol reduced the incidence of colon cancer in rats.
2. Description of the Related Art
Colon cancer is a leading cause of death among patients with internal malignancies in the United States and, unfortunately, at the time of initial diagnosis is incurable in approximately one-half of the patients found to harbor this malignancy (Zarling and Rhodes, Int. Med. Specialist 3:72-86, 1982). Moreover, despite advances in the fields of surgery, radiotherapy and chemotherapy, the cure rate for this disease has not improved significantly (Zarling and Rhodes, 1982). Based on these considerations, the search for strategies to prevent the development of cancers in this organ has markedly intensified during the past decade.
Although the cause of large bowel cancer is not known, most epidemiologists associate it with diet, and, in particular, the low-fiber, high-protein, high-fat content that characterizes the diet of most Americans and people in other urban, industrialized societies. Many observers believe that colon cancer is the first major cancer type for which available evidence is sufficient to recommend dietary changes in the general public (Willett, Nature 338:384, 1989; Greenwald, Cancer 70 (Suppl.): 1206, 1992). In this regard, the possibility of using dietary supplements as a strategy to prevent colon cancer has recently been recognized (Mukhtar and Athar, Clev. Clin. J. Med. 55:507-508, 1988).
During the past few years one such potential dietary supplement, vitamin D.sub.3, has received increasing attention. Data has accumulated from a number of different sources in support of the possibility that vitamin D.sub.3, or its metabolites, may play a preventive role in the development of colon cancer. Several epidemiological studies (Garland et al., Lancer 1:307-309, 1985; Garland et al., Int. J. Epidemiol. 9:227-231, 1980; Garland et al., Lancet II:1176-1178, 1989, Garland et al., Am J. Clin. Nutr. 54:193S-201S, 1991), for example, have suggested that vitamin D.sub.3 derived from the diet or from cutaneous synthesis due to sunlight exposure may decrease the risk of colon cancer in humans. Additionally, vitamin D.sub.3 dietary supplementation has been shown to inhibit the incidence of colon carcinogenesis induced by the administration of 1,2-dimethylhydrazine (DMH) in rats fed a high fat diet (Pence and Buddingh, Carcinogenesis (Lond) 9:187-190, 1988).
Both the vitamin D.sub.3 metabolites, 1.alpha.-hydroxyvitamin D.sub.3 (1.alpha.(OH)D.sub.3) (Kawaura et al., Carcinogenesis (Lond) 10:647-649, 1989, Kawaura et al., Cancer Lett. 55:149-152, 1990) and 1.alpha.,25-dihydroxyvitamin D.sub.3 (1.alpha.,25(OH).sub.2 D.sub.3) (Belli et al., Carcinogenesis 13:2293-2298, 1992), have also recently been shown to protect against the development of chemically-induced colonic tumors. Furthermore, 1.alpha.,25(OH).sub.2 D.sub.3 has been demonstrated to inhibit the proliferation of a number of malignant cell lines in vitro (Colson et al., Endocrinology 108:1083-1086, 1981, Lointier et al., Anticancer Res. 7:817-822, 1987, Niendorf, et al., J. Steroid Biochem. 27:815-828, 1987, Tanaka et al., Arch. Biochem. Biophys. 276:415-423, 1990, Halline et al., Endocrinology 134:1710-1717, 1994), including several derived from human colon adenocarcinomas (Lointier et al., 1987, Niendorf et al., 1987, Tanaka et al., 1990, Halline et al., 1994).
While these studies have suggested that vitamin D.sub.3 or one or more of its metabolites may prevent colon cancer, there is considerable concern about their potential toxicity, particularly with respect to elevation of serum Ca.sup.2+ levels and its consequences, such as deposition of this mineral in soft tissues (Kawaura, et al., 1989, Belli, et al., 1992, Anzano, et al., Cancer Res. 54:1653-1656, 1994).
Recently, a fluorinated derivative of vitamin D.sub.3, 1.alpha.,25(OH).sub.2 -16-ene-23-yne-26,27 F.sub.6 -vitamin D.sub.3 (RO24-5531), was found to inhibit proliferation of HL-60 cells (Zhou et al., Blood 78:15-82, 1991), presumably because substitution of fluorine atoms on C-26 and C-27 inhibits its metabolism and prolongs its actions (Anzano et al., 1994; Zhou et al., 1991). Moreover, RO24-5531 extended breast tumor latency and lessened tumor incidence as well as tumor number, without causing elevated levels of serum Ca.sup.2+ in these animals (Anzano et al., 1994).
In comparing breast and colon cancers, however, epidemiologic differences appear when various risk groups are studied. For example, in the United States, while Japanese immigrants have colon cancer rates similar to the Caucasian population, breast cancer rates take several generations to approach those of the resident population (Hanai et al., Nat. Can. Inst. Monograph 62:3-7, 1982, Haenszel, 1982). In a related study, the rates of breast cancer among Seventh-Day Adventists were similar to those in the general population, but rates of colon cancer were about 40% lower (Phillips et al., J. Natl. Cancer Inst. 65:1097-1107, 1980). In case-controlled and prospective cohort studies of colon and breast cancer, research indicated that clear associations were found between fat or meat intake and colon cancer, but not breast cancer, in each pair of analyses (Phillips, Cancer Res. 35:3513-3522, 1975; Willett et al., New Engl J. Med. 316:22-28, 1987). The treatment methods for colon cancer, of which more than 99% are adenocarcinomas, are generally different from those used for breast cancer treatment. In summary, with respect to natural history, epidemiological studies and treatment strategies, breast and colon cancer are substantially different.
While epidemiologic evidence implicates diet as a major etiologic factor for colorectal cancer, there exists a great need for a dietary supplement or anticarcinogen to prevent the primary initiation of tumorigenesis, without causing toxicity.